Vaccine research represents shift in TB fight

Scientists are learning more about how the body fights tuberculosis in an effort to build immunity

While scientists and drug-makers work to bring new antibacterial treatments to the market in response to the emergence of drug-resistant tuberculosis, some researchers are trying another approach: a vaccine.

"All the drugs that we have, and the new ones we're developing, are strain-specific," said Willem Hanekom, laboratory director of the South African Tuberculosis Vaccine Initiative. Once the bacterium mutates, developing resistance to the drug, the drug is useless. Vaccines are likely to induce or cause immunity which would work across all strains.

New drugs are still needed now, though, Hanekom said. "A vaccine is a very long-term solution," he said. "It's not going to happen overnight." Also, all current vaccines are preventive; if you already have the disease, you need other means to treat it.

More than one-third of the people in the world carry the TB bacterium (Mycobacterium tuberculosis) in their bodies, usually acquired by breathing it in after someone has coughed it into the air. In most of us, the bacterium remains dormant; in about one in ten the infection will activate and become TB, often because the immune system already is weakened by another disease, such as HIV. If untreated, the disease kills more than half its victims, according to the World Health Organization (WHO). Treatment, with painful shots and daily regimens of dozens of pills, can last six months or more.

Resistance grows

One of the reasons for the growing number of strains of multi-drug-resistant TB is that people stop their treatment early, beating down the bacteria in their systems but not killing them. The bacteria that survived reproduce, and the next time the person feels sick and uses the same medicine it will not work as well, or at all. These are the bacteria they cough into the air, infecting others.

"Unless you treat TB correctly, this resistance develops," Hanekom said. "One of the biggest problems with TB is that patients start feeling better after a month, and they can't understand why treatment should go on for six months." That is why the WHO and other public-health groups recommend enlisting clinical workers and family members to watch and make sure an ill person takes all the right medicines the whole time.

"One of the biggest problems with TB is that patients start feeling better after a month, and they can't understand why treatment should go on for six months."

"All new TB drug-susceptible cases may one day become resistant to one drug if the treatment that is given is not adequate," said Mario Raviglione, an infectious disease specialist and the director of WHO's Stop TB project. "And the problem is that these people are also infectious to others, so it's not just a matter of developing resistance in one individual affected by TB, but the potential that this person will have transmitted the disease-resistant bacilli to others."

More than 2 million people worldwide die of the infection each year, and nearly 9 million become sick, according to the World Health Organization. While there had been some reports of multi-drug-resistant strains earlier, the wake-up call for many was a report in The Lancet in 2006 about an outbreak in Tugela Ferry, South Africa, of a strain of extensively drug-resistant tuberculosis (XDR-TB). Of 544 patients who had TB, 53 were found to have XDR-TB; 52 of them died within 25 days of the appearance of symptoms.

There have been reports of XDR-TB cases in 37 countries, including a U.S. citizen in Italy who traveled through several countries on his return to the United States. Although XDR-TB is not considered more virulent or contagious than other forms of tuberculosis, it is far more difficult to cure because it is resistant to nearly all the antibiotics normally used for TB, is far more difficult and expensive to cure. Only about 30 percent of people who contract XDR-TB and are treated are cured, according to the Centers for Disease Control and Prevention (CDC).

At present, the rate in the United States is low. Between 2000 and 2006, there were 17 cases of people with XDR-TB in the United States, the CDC reported. However, in some developed and developing countries the rate of people contracting XDR-TB is much higher. Of the roughly 275,000 people who develop TB each year in Western Cape Province, South Africa, where researcher Hanekom works at the University of Cape Town, more than 2,000 have MDR strains and 45 have XDR strains of the pathogen.

Looking for clues

Hanekom and his colleagues are working to define exactly what in the immune system they can measure to say whether a person is protected or not protected against TB. "It sounds really silly that we don't know this in 2007," he said. "But we don't." (Robert Koch discovered the M. tuberculosis bacteria 125 years ago.) Once they discover what parts of the system are most important, they and other researchers can use these tests to evaluate new vaccines efficiently, and possibly guide vaccine design to specifically cause that kind of immunity, he said.

Hanekom’s lab is part of consortiums of labs in Africa, North America and Europe that share their discoveries and data, especially on immune-system T cells, which fight bacteria and direct the work of other fighters.

Currently, there is only one TB vaccine, called Bacille Calmette-Guerin (BCG). It is effective at preventing severe TB in infants, but not at preventing TB of the lung, which is the form of the disease that results in spread of the pathogen.

It is not generally recommended in the United States because the number of cases of TB is so low, according to the Centers for Disease Control. In places like South Africa, where TB is common, the vaccine is given because it is 80 percent effective at preventing TB meningitis, a devastating central nervous system complication.

Hanekom has collected blood samples from BCG-vaccinated babies to look at the role of a subset of white blood cells, called regulatory T cells, in immunity caused by the vaccine. What he found surprised him.

"We found that yes, regulatory T cells were induced (caused) by the vaccine. But there were three different types of them, and they were very distinct types." They want to follow up, looking at the same cells in deeper detail, he said. (Part of this research was funded by the Dana Foundation.)

What they have learned now, though, can be immediately applied to other studies in the consortium helping them sharpen the questions they ask. Hanekom also is investigating how immunity caused by the BCG vaccine acts in some children to protect against TB while in others it does not. To do this, the South African Tuberculosis Vaccine Initiative has collected blood samples from more than 5,000 infants 10 weeks after their newborn BCG vaccination.

Initiative members are tracking which of the vaccinated children later developed TB, (and so apparently were not protected by BCG) and which infants remained healthy despite exposure to adult TB (protected by BCG). Hanekom’s group then tests the blood samples, looking for differences.

"Our work is to define exactly what in our immune system can protect us against tuberculosis," Hanekom said. "That we know so little now is a big problem."